Background

Adolescents have been involved in trials for vaccines to prevent
sexually transmitted infections/diseases like Human Papilloma Virus
(HPV) and Herpes Simplex Virus type-2, (HSV-2), both in the developed
and the developing world [1,2].
In Merck's ongoing quadrivalent HPV vaccine program, at least 12 000
young people between the ages of 9–24 have received the HPV vaccine,
with approximately 20% of these being boys and girl between the ages of
9–15 (Merck, personal communication). Infants have also participated in
phase I HIV vaccine trials and currently Uganda is enrolling HIV
exposed infants in a phase I vaccine trial [3,4]. However, no HIV uninfected adolescents have participated in HIV vaccine trials anywhere in the world.

Because adolescents are severely affected by the HIV epidemic [5-7],
they should be the main recipients/beneficiaries of a successful HIV
vaccine. To achieve this, there will be a need to license the vaccine
for use in this age group. Adolescent participation in HIV vaccine
trials is therefore paramount in order to determine the safety profile,
appropriate dosing schedules and the degree of immunogenicity in this
age group. Adolescent trials are also necessary as vaccine responses
may differ because of physiological or hormonal differences between
adults and younger adolescents [8,9].
Delays in licensure for use in adolescents could retard the control of
the HIV epidemic, as was seen in the control of the Hepatitis B
epidemic in the United States where there was no clear strategy to
include infants, children and adolescents in the vaccination program [10].

South African researchers anticipate enrolling 16–18 year olds in a
phase IIb proof of concept vaccine trial towards the end of 2007. These
adolescents will be at high risk of HIV infection. Further, it is
envisaged that 12–15 year old adolescents will be involved in phase
I/II trials as early as 2008. The phase I/II studies will determine the
safety, tolerability and preliminary immunogenicity in pre-teens and
young adolescents of candidate vaccines that are currently being tested
for preliminary efficacy in adults and older adolescents. The phase
I/II studies will involve a small number of healthy adolescents, at low
risk of acquiring HIV infection.

In the development and review of adolescent HIV vaccine protocols,
there are many legal complexities that need to be addressed. This
article sets out complexities linked to consent requirements; special
legal protections for children in need of care and protection; and
procedural requirements for the approval of such research. These
complexities are not unique to South Africa because in many
jurisdictions where such trials may occur adolescent participants will
have limited legal capacity, and the enrolment of adolescents must take
account of local laws dealing with, for e.g., the age of lawful consent
to sex and obligations on certain adults to report abuse. Furthermore,
like South Africa, very few developing countries will have dedicated
research laws. Therefore this article also discusses implications of
these legal complexities for role-players in other jurisdictions. We
make a series of recommendations for additional work that needs to be
done in order to realize the optimal involvement of adolescent
participants. We refer to "child" as a person under the age of 18 [11,12] and a "minor" as a person under the age of 21 [13] soon to change to 18 [14]. We use the term "adolescent" to refer to persons between the ages 12 and 18 [15].

HIV vaccine trials

Phase I/II HIV vaccine trials with adolescents would aim to recruit
a small number of healthy adolescents who are at low risk of acquiring
HIV infection. Phase IIb trials will recruit adolescents at higher risk
of HIV infection. The trials themselves will comprise of a number of
interventions, including a general physical examination and medical
history-taking; assessment of HIV risk factors including personal
questions about sex and substance use; personalized risk reduction
counseling; administration of an experimental HIV vaccine or placebo
via injection; blood draws for laboratory safety and immunogenicity
testing; and regular testing for HIV infection. Adolescents will be
classified as "low risk" if they are not sexually active as defined as
primary abstinence (no sexual activity ever initiated) or secondary
abstinence (no sexual activity for six months). Although many
interventions in a phase I trial may not hold out the prospect of
direct benefit for adolescent participants, there are interventions
that may benefit participants, such as personalised risk reduction
counselling. Additionally, there may be associated benefits such as
identification of medical conditions like hypertension and early
referral to care, access to care for intercurrent illness or
reproductive health, and referral for abuse. Despite conceptual
difficulties in classifying whole protocols as either "therapeutic" or
"non-therapeutic research" [16]
it is possible that phase I safety trials in South Africa would be
classified as "non-therapeutic" because of the preponderance of
interventions that will not confer direct benefit.